Secondary metabolites are a crucial source of bioactive compounds playing a key role in the development of new pharmaceuticals. Recently, biosynthetic research has benefited significantly from progress on various fronts, including reduced sequencing costs, improved genome/metabolome mining strategies, and expanding tools/databases to compare and characterize chemical diversity. Steady advances in these fields are crucial for research on non-modal organisms such as lichen-forming fungi (LFF). Although most fungi produce bioactive metabolites, biosynthetic research on LFF (c. 21% of known fungi) lags behind, primarily due to experimental challenges. However, in recent years, several such challenges have been tackled, and, in parallel, a critical foundation of genomic data and pipelines has been established to accomplish the valorization of this potential. Integrating these concurrent advances to accelerate biochemical research in LFF provides a promising opportunity for new discoveries. This review summarizes the following: recent advances in fungal and LFF omics, and chemoinformatics research; studies on LFF biosynthesis, including chemical diversity and evolutionary/phylogenetic aspects; and experimental milestones in LFF biosynthetic gene functions. At the end, we outline a vision and strategy to combine the progress in these research areas to harness the biochemical potential of LFF for pharmaceutical development.
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